title: Pharmacokinetics of afatinib, a selective irreversible ErbB family blocker, in patients with advanced solid tumours.
abstract: OBJECTIVE
  Afatinib is a potent, irreversible, ErbB family blocker in clinical development for the treatment of a variety of solid tumours. This study evaluated the pharmacokinetics of afatinib (10-100 mg once daily) in cancer patients.
  
  
  METHODS
  Data from 221 patients with advanced solid tumours in four phase I and one phase II trial were analysed using non-compartmental methods.
  
  
  RESULTS
  Within each dose group, the shape of the geometric mean plasma concentration-time profiles after single and multiple doses were comparable. Maximum plasma concentration (C(max)) values were achieved 2-5 h after dosing and thereafter declined at least bi-exponentially. Steady-state plasma concentrations were attained within 8 days after the start of dosing. The geometric mean terminal elimination half-life at steady state was about 37 h. Repeated dosing resulted in a 2.77-fold accumulation based on the area under the plasma concentration-time curve (AUC), and 2.11-fold accumulation based on C(max) values. A slightly more than dose-proportional increase in afatinib exposure was observed. There was moderate intra-individual variability in afatinib trough concentration values (the geometric coefficient of variation (gCV) ranged from 22.2 to 67.5 %). The inter-patient variability in plasma concentrations was moderate to high (e.g. at the 40 mg dose, the gCVs ranged from 35.6 to 221 %). The exposure to afatinib (as measured by AUC and C(max)) correlated with the severity of the most common adverse events of afatinib--diarrhoea and rash.
  
  
  CONCLUSIONS
  The pharmacokinetic profile of afatinib supports a once-daily dosage regimen. As expected for this patient population, the pharmacokinetic parameters of afatinib showed moderate to high inter-patient variability. Afatinib exhibits non-linear pharmacokinetics.
authors.affiliation: Translational Medicine, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany, sven.wind@boehringer-ingelheim.com.
authors.forename: Sven
authors.initials: S
authors.lastname: Wind
authors.forename: Marion
authors.initials: M
authors.lastname: Schmid
authors.forename: Julia
authors.initials: J
authors.lastname: Erhardt
authors.forename: Rainer-Georg
authors.initials: RG
authors.lastname: Goeldner
authors.forename: Peter
authors.initials: P
authors.lastname: Stopfer
mesh_terms: D000293:Adolescent; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood*; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000097:blood / Q000493:pharmacokinetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D000077716:Afatinib; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human